A Biomaterial Niche of Satellite Cells for Skeletal Muscle Regeneration In response to minor injuries, skeletal muscles exhibit a remarkable regenerative capacity empowered by satellite cells (SCs), a stem cell population localized along the surface of muscle fibers under the basal lamina. However, in the case of severe muscle injuries resulting from trauma, surgery, or disease, this natural healing process does not occur. Current cell-based therapies are hindered by limited functional improvement resulting from low survival and long-term engraftment of the transplanted cells due to the lack of appropriate supportive microenvironment in the injured muscle. Thus, there is a critical need for the development of a bioengineering strategy to provide cellular and structural support in regeneration of new functional muscles. SC niche provides a local microenvironment imbued with a complex network of signals that regulate the self-renewal, proliferation, and myogenic differentiation of SCs. The goal of this proposal is to develop a bioengineered cell niche offering appropriate structural and mechanical support for SCs to facilitate muscle regeneration. Our goal will be achieved by performing the following specific aims: Aim 1: To create a polymeric platform of aligned fiber matrices mimicking anisotropic organization of muscular tissue. Aim 2: To optimize scaffold properties with a focus on scaffold fiber diameter and stiffness to enhance cellular responses including attachment, self-renewal, proliferation, and differentiation of SCs. Aim 3: To evaluate the in vivo regenerative efficacy of the SCs seeded on the optimized fiber scaffold in supporting muscle regeneration. Our overall hypothesis is that a synthetic scaffold with appropriate structural and mechanical properties will act as a bioengineered niche to support SCs for accelerated muscle regeneration. Successful completion of the project will provide an understanding of the biomaterial regulation of SCs and pave the way for the development of an effective muscle regenerative device to treat muscular diseases.